Rheumatology Connections - Cleveland Clinic · 2013. 12. 20. · collaboration makes me feel honored to work with my 32 rheumatology colleagues at Cleveland Clinic. I hope you enjoy

Rheumatology Connections

An Update for Physicians | Fall 2013

Advancing Rheumatology Through Biobanking 3 | Rituximab in GPA: To Add or Not to

Add Another Agent? 4 | In Search of Biomarkers in GPA 6 | Are Microparticles the Link

to Atherosclerosis in GPA? 8 | In Appreciation of ... the Urinalysis 9 | Osteoporosis

Outcomes 11 | Multidisciplinary Clinics Make a Difference in Lupus, Fibromyalgia 12, 14

Biologics, Vasculitis Courses 16 | Updating The Netter Collection 18 | Clinical Trials 19

Dear Colleagues,

I’m pleased to share this issue of Cleveland Clinic’s Rheumatology Connections with you. The articles here demonstrate the exciting synergy that results from collaboration among the members of the Department of Rheumatic and Immunologic Diseases and with their colleagues beyond the department.

These fruitful “connections” are evident throughout the issue:

• Dr.ElaineHusniprofilesourbiobankenterprise,whichisgeneratingexcitingopportunitiesforbiomarkerresearchintotheetiologyofcardiovasculardiseaseinpsoriaticarthritis,immuneregulationingranulomatosiswithpolyangiitis(GPA;Wegener’s),andbiomarkeranalysisinreversiblecerebralvasoconstrictionsyndrome and lupus (page 3).

•Dr. Carol Langford and Dr. Gary Hoffman’s collaboration with trainees has furtheredourunderstandingoftheefficacyofmaintenancetherapyafterrituximabtreatment for GPA (page 4).

• ThecollaborativeworkofDr.AtulKhasnishasshedlightonimmunologicperturbations in patients with GPA (page 6).

• Emerging discoveries about the role of microparticles in the etiology of atherosclerosisinpatientswithGPAhavebeenmadepossiblebytheworkof Dr. Rula Hajj-Ali and colleagues (page 8).

• The efforts of many specialists from across Cleveland Clinic have expanded opportunitiesinpatientcare,researchandeducationthroughourmultidisciplinaryLupus Clinic (page 12).

•UnderthedirectionofDr.CarmenGota,ClevelandClinic’sinterdisciplinaryFibromyalgia Clinic has created new treatment paradigms for the management of a therapeutically challenging condition (page 14).

• ThefifthBiologicTherapiesSummit,heldearlierthisyearunderthedirectionofDr.LeonardCalabrese,wasasuccessthankstothecollaborationofmanystaffinthe department as well as rheumatologists and specialists from around the world (page 16).

It is the synergy from collaboration that has yielded these diverse and dynamic projectsinscientificdiscovery,patientcare,clinicalresearchandeducation.Thatcollaborationmakesmefeelhonoredtoworkwithmy32rheumatologycolleagues atClevelandClinic.Ihopeyouenjoyreadingabouttheirwork.Pleasecontactmewith your questions or comments.

Happy Holidays!

AbbyAbelson,MD Chair,RheumaticandImmunologicDiseases 216.444.3876 | [email protected]

Rheumatology Connections,publishedbyCleveland Clinic’s Department of Rheumatic and Immunologic Diseases,providesinformationonleading-edgediagnosticand management techniques as well as current research for physicians.

Please direct any correspondence to:

Abby Abelson, MD Chair,RheumaticandImmunologicDiseases

Cleveland Clinic/A50 9500 Euclid Avenue Cleveland,OH44195

Phone: 216.444.3876

Email: [email protected]

Managing Editor: Glenn Campbell

Graphic Designer: BarbaraLudwigColeman

Photography: NeilLantzy,MatthewKohlmann, SteveTravarca

To view the staff directory for the Department of Rheumatic andImmunologicDiseases,visitclevelandclinic.org/rheum.Forahardcopy,[email protected].

Rheumatology Connections is written for physicians and should be relied on for medical education purposes only. It does not provide a complete overview of the topics covered and should not replace the independent judgment ofaphysicianabouttheappropriatenessorrisksofaprocedure for a given patient.

© The Cleveland Clinic Foundation 2013

From the Chair of Rheumatic and Immunologic Diseases

Cleveland Clinic’s Rheumatology Program is ranked among the top 2 in the nation in U.S. News & World Report’s “America’s Best Hospitals” survey.

For referrals, call 855.REFER.123 (855.733.3712)Page 2 | Rheumatology Connections | Fall 2013

How Can Biobanking Advance Rheumatology Practice?The Rationale and Early Payoffs of Comprehensive Efforts at Cleveland ClinicBy M. Elaine Husni, MD, MPH

Thephysicianleadersofourbiobankgroup(lefttoright): RulaHajj-Ali,MD;MehrnazHojjati,MD;ElaineHusni,MD,MPH;andAtulKhasnis,MD,MS.

BiobankingisanincreasinglyintegralpartofCleveland Clinic’s Department of Rheumatic andImmunologicDiseases.Asscientificresearch places further emphasis on im-provingindividualizedcare,orpersonalizedmedicine,thescienceofbiobankingcanprovide clues and insights to improve patient outcomes.Afterbrieflyoutliningtheessen-tialsandbenefitsofbiobanking,thisarticle

profilestheseveralactivebiobanksmanagedbyourdepartment.

All About Matching Specimens with Clinical Data

Biobanks,orbiorepositories,storebiologicalspecimens,suchasblood,plasmaandurine,andcombinethemwithcorrespondingclinical data from the individuals who supplied the specimens. This biorepositoryofdatalinksvaluable,highlyspecific,de-identifiedhealth information to individual biosamples. Through this combina-tionofspecimensandcomprehensiveclinicalinformation,biobanksprovide a structured and novel way to match clinical data with bio-logical samples.

Beyondthiscoreutility,biobanksalsoserveasexceptionalnet-work-buildingtools,allowingresearcherswithsharedintereststoconnect and collaborate in disease investigation.

Good Governance Is Paramount

Thesuccessofbiobanksrequiresplanningandorganization,asstorage procedures and longitudinal data collection can be complex anddemandscrupulousattentiontoethicalprinciplesandscientificintegrity.AtClevelandClinic,abiobankgoverningcommitteeisre-sponsibleforreviewingthescientific,legalandethicalcomponentsofaproposedbiobankstudywhileensuringadherencetoIRBpoli-cies and procedures for protection of human research subjects.

BecausetheDepartmentofRheumaticandImmunologicDiseasesincludes numerous researchers involved in the collection and stor-ageofhumanbiospecimensinavarietyofrheumaticdiseases,ourgroupholdsquarterlybiobankmeetingstoestablishguidelinesandbestpracticesformanagingourbiobanks’dailyoperations.Wealsohavetwobiobankcoordinators,LoriStrozniakandKellyGoodrich,whohelpimplementbiobankresearchprotocolsandinteractwithresearch participants to obtain informed consent and handle recruit-ment,enrollmentandfollow-up.

Promoting Early Detection of Cardiovascular Disease in PsA

ElaineHusni,MD,MPH,andcolleaguesareusingbiobankresourcesto recruit participants with psoriatic arthritis (PsA) who consent to

provide blood and urine samples and longitudinal clinical data. PsA isaheterogeneousdisorderassociatedwithinflammatoryarthritisandskinpsoriasis.Many,butnotall,patientswithPsAareatin-creasedriskforcardiovasculardisease,sodetectingthosewhoaremay promote earlier treatment and improved outcomes.

ThePsAregistryisourlargestbiorepository,securelystoringmorethan1,000biosamplesanddataonnearly200patients.Itisfocused oncorrelatingclinicaldatawithserumbiomarkersofcardiovascularinflammation,subclinicalmeasuresanddiseaseactivity.

Probing Immune Dysfunction in GPA (Wegener’s)

AtulKhasnis,MD,MS,hasteamedwithcolleaguesatCaseWest-ern Reserve University to investigate granulomatosis with polyangiitis (GPA;Wegener’s),anunusualmultisystemdiseasecharacterizedbyinflammationofsmallandmedium-sizebloodvesselsinvariousorgansthatcanleadtoischemia,hemorrhageandorganfailure.

Centraltohiseffortsisbiobanking—specifically,collectingandexamining serum biosamples with the aim of better understanding dysfunction of the immune system in GPA. With the advent of biologicallytargetedtherapiessuchasrituximab,whichisFDA- approvedforthetreatmentofGPA,thereisagreaterneedtoun-derstand the impact of such treatments on the immune system in thisandsimilarcomplexillnesses.SeethefullarticleonDr.Khasnis’workinthisareaonpage6.

Providing More Clues in CNS Disorders

RulaHajj-Ali,MD,andherteamarestudyingreversiblecerebralvasoconstrictionsyndrome(RCVS)andcentralnervoussystem(CNS)vasculitis.RCVScomprisesagroupofdiverseconditions

Visit clevelandclinic.org/rheum Rheumatology Connections | Fall 2013 | Page 3

Rituximab-Induced Remission in Granulomatosis with Polyangiitis:To Add or Not to Add a Conventional Maintenance Agent?Retrospective Data from 110 Patients

By Lama Azar, MD; Jason Springer, MD; Carol A. Langford, MD, MHS; and Gary S. Hoffman, MD, MS, MACR

Rituximab (RTX) is an effective remission-inducing agent in granulo-matosis with polyangiitis (GPA; Wegener’s). It is uncertain whether RTX is best used with or without a conventional agent for remission maintenance.Toexplorethisquestion,ClevelandClinic’sCenterforVasculitis Care and Research conducted a single-center retrospec-tivestudytoassesstheefficacyandsafetyofRTXinductiontherapyin patients in whom RTX was used alone vs. in combination with a conventional maintenance agent.

Study Design at a Glance

We retrospectively analyzed data on all patients with GPA treated byourcenterwithatleastonecourseofRTX(fourweeklydosesof 375 mg/m2IV,ortwofixeddosesof1,000mgIVtwoweeksapart)untilNovember2011.RemissionwasdefinedasaBirming-hamVasculitisActivityScore(modifiedforWegener’s)of0.

Results

Inall,110patients(medianage,50years;51percentwomen)wereincluded(Figure1).In91percent,theindicationforthefirstRTXinfusionwasrelapsingorpersistentdisease.Medianfollow-upwas23months(interquartilerange[IQR],10-50).

Complete remission was achieved in 97 percent of patients. Relapses occurredin47percent,andthemediantimetorelapsewas13months(IQR,7-20.5).Withinasubsetof16patientswhowererelapse-freeattwoyearsafteroneRTXcourse,remissionsenduredfor two to six years in eight patients.

Relapse-freesurvivalwassignificantlyhigherinpatientsreceivingaconventionalmaintenanceagent(azathioprine[AZA],methotrexate[MTX]or,ifAZAorMTXwerenottolerated,mycophenolatemofetil[MMF])inconjunctionwithRTXandglucocorticoids(n=49)than

characterized by reversible multifocal narrowing of the cerebral arteriesheraldedbysudden,severe(thunderclap)headacheswithorwithoutassociatedneurologicdeficitsand—mostimportant—byreversibleangiographicfindings.RCVSisofmajorimportancetorheumatologistsbecauseitistheleadingmimicofCNSvasculitis.EarlyrecognitionanddiagnosisofRCVScansavepatientstherisksof unnecessary immunosuppression.

Wearenowbuildingarepositoryofclinicaldata,radiologicfindingsandbiologicalsamplesfrompatientswithRCVSandCNSvasculitis.ByinvestigatingbiomarkerstohelpdiagnoseRCVSanddeveloptherapeutictargets,wehopetobetterdistinguishRCVSfromothercerebralarteriopathies,bothinflammatoryandnoninflammatory.

Improving Outcomes in Patients with Lupus

MehrnazHojjati,MD,andcolleaguesaredirectingClevelandClinic’s lupus registry. A great deal of what we have learned about lupus over the past decade has originated from large patient data-bases and registries.

The primary goal of the lupus registry is to facilitate interaction be-tween the realms of basic research and clinical medicine. With this registry we aim to analyze factors potentially involved in disease onset,therapeuticeffectivenessanddevelopmentofdiseasecom-plications.Wealsoaimtoanalyzeurineandbloodforbiomarkersthat may predict disease activity and potential organ involvement.

A Bright Future for Biobanks

Thefutureofbiobankingisfullofpromiseandpossibilities.Thenetworkingopportunitiesandresourcesthatbiobanksprovidearepriceless,andtheyopenthedoorforcollaborationswithcolleaguesnear and far.

Dr. Husni is Director of the Arthritis and Musculoskeletal Center and Director of Clinical Outcomes Research for the Department of Rheumatic and Immunologic Diseases. She can be reached at [email protected] or 216.445.1853.

Forreferrals,call855.REFER.123(855.733.3712)Page 4 | Rheumatology Connections | Fall 2013

inthosenotreceivingamaintenanceagent(n=43)(P=.04)(Figure2).Thehazardratioforrelapsewas0.54(95%confidenceinterval,0.30-0.99)inthosereceivingasecondagentforremis-sion maintenance.

Seriousadverseeventsdidnotdifferbetweenthetwogroups.

Implications Until Prospective Trials Are Performed

Addition of a conventional maintenance agent to RTX and glucocor-ticoids reduced the incidence of GPA relapse without resulting in a higher incidence of adverse events. Prospective trials comparing conventional immunosuppressive maintenance agents with repeated scheduledRTXdosesareneeded.Untilthosedataareavailable,ourfindingssupporttheadditionofaconventionalmaintenanceagent(AZAorMTX),intheabsenceofcontraindicationsorintoler-ance,toreducetheriskofGPArelapse.

This research was originally presented by Dr. Azar at the 2012 American College of Rheumatology Annual Meeting.

Dr. Azar completed a rheumatology fellowship in the Department of Rheumatic and Immunologic Diseases in 2013.

Dr. Springer completed a vasculitis fellowship in the Department of Rheumatic and Immunologic Diseases in 2013.

Dr. Langford is Director of the Center for Vasculitis Care and Research as well as Vice Chair for Research, Department of Rheumatic and Immunologic Diseases. She can be reached at [email protected] or 216.445.6056.

Dr. Hoffman is the founder of the Center for Vasculitis Care and Research and a staff member in the Department of Rheumatic and Immunologic Diseases. He is also Professor of Medicine, Cleveland Clinic Lerner College of Medicine. He can be reached at [email protected] or 216.445.6996.

Figure 1. Disease course and additional therapies afterthefirstRTXtreatment(RTX1).Theadditional immunosuppressive agent used was eitherazathioprine(AZA),methotrexate(MTX)or,ifAZAorMTXwerenottolerated,mycophenolatemofetil(MMF).

110 patients with GPA received RTX1

Active disease(n = 105)

Remission-maintenance(n = 5)

Death (n = 1) Change in treatment plan (n = 1) Lost to follow-up (n = 1)

Treatment failure (n = 2)

Partial remission Complete remission (n = 1) (n = 99)

n = 105

Did not receive pre-emptive retreatment with RTX to maintain remission

(n = 92)

Retreated pre-emptively with RTX to maintain remission

(n = 13)

No additional immunosuppressive agent used after RTX/glucocorticoids

(n = 43)

Additional immunosuppressive agent used after RTX/glucocorticoids

(n = 49)

Until prospective data are available, our findings support the addition of a conventional maintenance agent to reduce the risk of GPA relapse.

100

0

80

40

20

60

Percentage of Patients Remaining in Remission

Months After Achieving Initial Remissionn = 49

P = 0.04

6 12 18 24

With additional agentNo additional agent

n = 43

Figure 2.Kaplan-Meieranalysisshowingrelapse-freeremissioninpatientstreated with RTX and glucocorticoids only (light blue line) vs. patients treated with RTX and glucocorticoids plus an additional immunosuppressive agent (darkblueline).TheadditionalagentwaseitherMTX(n=12),AZA(n=29)orMMF(n=8)(seeFigure1forabbreviationexpansions).


In Search of Biomarkers:

Collaboration to Study Immunologic Perturbations in Granulomatosis with Polyangiitis Looks to Ultimately Guide TherapyBy Atul Khasnis, MD, MS

Cleveland Clinic’s Center for Vasculitis Care and Research each year manages more than 500 patients with granulomatosis with polyangiitis (GPA; Wegener’s). This patient volume confers a responsibility to study GPA while also positioning us well to do so. Oureffortsinthisareaincludeadistinctiveongoing collaboration with Case Western ReserveUniversity(CWRU),profiledbelow,

to prospectively study immunologic perturbations in GPA.

Unmet Needs in Our Understanding of GPA

GPA is an uncommon but potentially life-threatening disease char-acterizedbygranulomatousinflammationand,typically,mediumand small vessel vasculitis. Affected patients experience serious morbidity from effects of the disease itself and the immunosup-pressive medications used to treat it. Patients and their physicians share a strong need to better understand this unusual and uncom-mon disease.

The immunologic underpinnings of GPA are incompletely understood. Anti-neutrophil cytoplasmic antibodies (ANCAs) are observed in GPA,buttheirroleinpathogenesisiscontroversial.Gainingim-munologic insights into GPA will enable better understanding of the mechanisms of disease onset and sustenance and the triggers of relapse. It will also help identify potential therapeutic targets. All of this will allow for better disease management and patient care.

Identificationofreliablebiomarkersofdiseaseactivityisalong-standing need in GPA. Comparing immunologic parameters during activediseaseandremission—animportantfocusofourresearchcollaboration—mayyieldinsightsintosuchpotentialbiomarkers.

The Research Project at a Glance

OurcollaborationwithCWRUisaprospectiveobservationalstudyfunded through Cleveland Clinic’s R.J. Fasenmyer Center for Clini-cal Immunology. Patients in the study are managed by their own rheumatologists while the research team periodically collects clini-cal data (captured in an electronic database) paired with blood samples for immunologic studies on a longitudinal basis. The blood samples are sent to the clinical research unit laboratory at Cleve-landClinic,wheretheyareprocessedforimmunologiccells,serumand plasma. These samples are then frozen and stored until they undergo immunologic analyses by two seasoned immunology labs at CWRU.

OurinterestliesinexaminingtheimmunesystemsofpatientswithGPAindetail,soweareanalyzingTcells,Bcells(Figure1),monocytesanddendriticcellsforphenotype,activation,exhaustionandcyclingbyflowcytometry.Inthefuture,basedonpreliminarydata,weplantoperformfunctionalstudiesonthesecellsubsetsin the hope of advancing our understanding of their role in disease pathogenesis. We plan to extend these immunologic studies to neutrophilsaswell,asneutrophilslikelyplayanimportantroleinGPApathogenesis.Oneunansweredquestioniswhetherimmuno-logicdisturbancesobservedinperipheralbloodaccuratelyreflectimmunologicperturbationsininflamedtissues.Whilewearenowperformingthesestudiesonperipheralblood,wehopetoperformrelevant studies on tissue samples obtained for clinically indicated reasons in the future.

Three Primary Research Goals

The project’s three main goals are:

•To study differences in patients’ immune systems during active GPA disease and remission. This will allow us to better under-standmechanismsthatdrivesystemicinflammationinGPA.WealsoplantosearchforB-cellsubsetsthatmayberesponsibleforANCAproduction.BycomparingtheimmunologicprofilesofactivediseaseandremissioninGPA,wehopetoidentifyclini-callyusefulimmunologicbiomarkersofdiseaseactivitythatcanbe validated in a patient population of appropriate sample size. Determining disease activity has implications for changing immu-nosuppression,whichisfraughtwithriskofmedicationtoxicity.Thustheidentificationofbiomarkerspromisestofacilitatethera-peuticdecision-making.

•To elucidate the effects of rituximab on the immune systems of patients with GPA.Rituximab(RTX),ananti-CD20monoclonalantibody(biologicagent),hasbeenapprovedbytheFDAfortreatment of GPA. Its main mechanism is thought to be elimina-tionofB-cellsubsetsthatbearCD20ontheirsurface.SinceBcells are part of the immune system(anetwork),itisplausiblethatdeletingBcellsmayhavequalitativeandquantitativeim-pact on other immune cells. We are attempting to evaluate the effectsofRTXbeyondB-celldepletion,suchaseffectsontheimmunologicprofilesofotherimmunecellsduringB-celldeple-tion and reconstitution. We are comparing patients who receive RTX with those who have received nonbiologic immunosuppres-sion,withtheaimofunderstandinganyuniqueimmunologicaspects of RTX-mediated immunosuppression in GPA.


•To identify predictors of relapse in GPA. GPA is a relapsing disease,andthecauseofrelapseisunknown.Ongoingrelapsescanleadtoaccrualoforgandamage,resultinginincreasedmor-bidityandsignificantimpactonqualityoflife.Sinceweplantoenrollpatientsduringremissionandfollowthemlongitudinally,we will have an opportunity to identify any consistent immuno-logicchangespredatingaflare(i.e.,“immunologicsignatures”)that could be used to guide therapeutic decisions once validated in an appropriately sized patient population.

BenefitsinExternalValidityandOngoingCollaboration

This project offers a unique opportunity to understand the patho-genesisofGPA.Becausethisisanobservationalstudyandnoneofitsclinicalmanagementdecisionsareinfluencedbytheresearchprotocol,itprovidesahighlevelofexternalvalidity(i.e.,real-world

applicability). It also represents an ongoing collaboration between twomajoracademicinstitutions,ClevelandClinicandCWRU,thatislikelytomeaningfullyadvanceourunderstandingofGPA.

The project’s other key investigators are Leonard Calabrese, DO, and Carol Langford, MD, MHS, of Cleveland Clinic and Michael Lederman, MD, and Donald Anthony, MD, PhD, of CWRU.

Dr. Khasnis is a staff physician in the Center for Vasculitis Care and Research and the R.J. Fasenmyer Center for Clinical Immunology, both in the Department of Rheumatic and Immunologic Diseases. He can be reached at [email protected] or 216.445.8156.

Figure 1.B-cellgatingstrategyforassessmentofB-cellsubsetfrequencies in patients with granulomatosis with polyangiitis (GPA; Wegener’s).


Granulomatosis with polyangiitis (GPA; Wegener’s) is characterized by necrotizing granulomatousinflammationandvasculitisof the small and medium-size blood ves-sels. Although survival of patients with GPA has improved with immunosuppressive therapy,atherosclerosishasemergedasasignificantGPA-associatedmorbiditythatisindependentoftraditionalcardiovascularrisk

factors.Coronaryarterydisease,strokeandperipheralarterialoc-clusive disease occur more frequently in patients with GPA than in healthycontrols.ThelinkbetweenGPAandatherosclerosisisnotwellcharacterizedatamechanisticlevel,butitraisesthepossibil-itythatpersistentlyactivevasculitis,ornonspecificinflammation,plays a role in early atherosclerosis.

Microparticles as Markers of Cardiovascular Risk

Anincreasingbodyofevidencesuggeststhat,inthecourseofsys-temicinflammation,cell-derivedmicroparticlesmaybeprognosticmarkersforthrombosis,atheroscleroticvasculardiseaseandsys-temicinflammation.Microparticlesaremembrane-boundvesiclesthatbudoffnormalcells,includingleukocytes,plateletsandvascu-larendothelialcells,duringactivationorapoptosis(Figure1).

Elevated levels of circulating microparticles have been shown to beassociatedwithcardiovascularriskandareindicativeofapoorclinical outcome. Circulating microparticle counts are increased in patientswithcardiovascularriskfactors.Moreover,microparticlecountsareanindependentmarkerofsubclinicalcarotidathero-sclerosis in asymptomatic subjects and may be more valuable for mortalityprognosisthanusualbiologicalmarkersofmyocardialinfarctionare.Inaddition,severalstudiespointtomicroparticles aseffectorsofvascularwallinflammation.

Microparticlesmaycontainpro-inflammatorymediators,suchasIL-1,andcaninteractdirectlywithactivatedvascularendothelialcells,triggeringmonocytearrestininflamedandatheroscleroticendothelium.Furthermore,microparticlescaninteractdirectlywithplatelets through the CD36 receptor (Figure 2). This raises the prospect of a novel mechanism for platelet-dependent monocyte recruitmentininflammationandatherosclerosis.

The Link with Rheumatic Diseases

Inrheumaticconditionssuchasrheumatoidarthritis,systemiclupuserythematosus,systemicvasculitidesandspecificallyGPA,microparticlecountscanpotentiallyserveasimportantmarkersofdisease activity.

Investigating Microparticles as a Likely Link Between Atherosclerosis and Granulomatosis with PolyangiitisBy Rula Hajj-Ali, MD

Figure 1.(left)Schematicillustrationofamicroparticle.

Figure 2.(below)Microparticles’interactionwithplatelets.


Inkeepingwithitsoverallmission,ClevelandClinic’sCenterforVasculitis Care and Research is studying the relationship between inflammatorydiseaseinGPAandthedevelopmentofatherosclerosis,with the aim of better understanding the pathogenesis of athero-sclerosisinGPA.Ourresearchfindingshavesuggestedthat(1)therecurrentinflammatoryburstthatoccursduringeachrelapseinpatients with GPA may have a direct role in the pathogenesis of ath-erosclerosis,and(2)levelsofcirculatingmicroparticlesareelevatedduring relapse and correlate with platelet reactivity.1

Our Latest Findings — and Implications

We recently further assessed the role of microparticles and their interaction with platelets and vascular endothelial cells in the pathogenesis of atherosclerosis in GPA.2Microparticlesisolatedfrom plasma of GPA patients were added at various ratios to human dermalmicrovascularendothelialcells(huDMVEC)andincubatedfortimedperiods.Cellswerethendetached,washed,resuspendedinbufferandanalyzedbyimmunofluorescenceflowcytometrywithanti-ICAM-1IgGtodetectendothelialcellactivation.Anisotope-matchedcontrolIgGwasusedascontrol.Inaddition,fluorescentlytagged normal human platelets were incubated with GPA patient-derived microparticles (at a microparticle-to-platelet ratio of 10-to-1),andplateletactivationwasdetectedbyflowcytometrywithPAC-1,anantibodytotheactivatedformoftheα2bß3 integrin.

This study found that:•MicroparticlesinduceICAMexpressiononhuDMVECs.

•Platelet surface expression of activated α2bß3 integrin was significantlyenhancedwhenplateletsfromhealthydonorswerepre-incubated with patient-derived microparticles.

Thesefindingsdemonstratethatmicroparticlesisolatedfromtheplasma of GPA patients can activate platelets and vascular endo-thelial cells. This suggests a possible role for microparticles as an interfacebetweeninflammationandatherothrombosisinGPA—apossibilitythatwelookforwardtoevaluatinginfutureinvestigations.

References

1.Hajj-AliR,SilversteinR,HoffmanG,ZhangL,ImreyP,LangfordCA. The correlation between circulating microparticles and platelet aggregation and disease activity in Wegener granulomatosis. Presented at:AmericanCollegeofRheumatologyAnnualMeeting;October2010;Atlanta,Ga.Arthritis Rheum.2010;62(10suppl):S856.Abstract2047.

2.Hajj-AliR,SilversteinRL,HoffmanGS,LangfordCA.Pathogenesisofatherosclerosis in granulomatosis with polyangiitis. Presented at: American CollegeofRheumatologyAnnualMeeting;November2012;Washington,D.C. Arthritis Rheum.2012;64(10suppl):S657.Abstract1537.

Dr. Hajj-Ali is a staff physician in the Center for Vasculitis Care and Research, Department of Rheumatic and Immunologic Dis-eases, with a special interest in systemic vasculitides and central nervous system vasculitis. She can be reached at [email protected] or 216.444.9643.

Onhospitalrounds,Iwasrecentlyasked, “If you could have only one test in a patient withsmallvesselvasculitis,whatwoulditbe?”Someweresurprisedbymyanswer: a urinalysis.

Tomymind,fewtestshavetheabilitytoprovide information that can detect and potentially prevent the presence of organ- and life-threatening disease the way a

urinalysiscan.Moreover,theurinalysisisatestthathasmeaning not only at diagnosis but throughout the patient’s course.

Glomerulonephritis is an important vasculitic manifestation that is typically asymptomatic. In granulomatosis with polyangiitis (Wegener’s)(GPA)andmicroscopicpolyangiitis(MPA),glomerulonephritiscanberapidandsevere,requiringdialysis,

which has a profound effect on patient quality of life and outcome. Glomerulonephritiscanalsooccurinotherformsofvasculitis,including eosinophilic granulomatosis with polyangiitis (Churg-Strauss),IgAvasculitis(Henoch-Schönlein)andcryoglobulinemicvasculitis.

Urinalysis and Serum Creatinine

Onemayask,iftheconcernisthekidneys,whywouldn’tmyonetest be a serum creatinine? There is no question that serum cre-atinineisimportant,asitprovidesameasureofrenalfunction.However,sinceanelevatedcreatininemeansthatmorethan50percentofrenalfunctionhaspotentiallybeenlost,thegoalistodetectglomerulonephritisbeforeacreatinineriseoccurs,whichtheurinalysisisabletodo.Inglomerulonephritis,theearliestfindingismicroscopichematuriawithdysmorphicredbloodcells,followed

In Appreciation of ... the UrinalysisIts Utility in Small Vessel Vasculitis Should Not Be Underestimated

By Carol A. Langford, MD, MHS


Figure 1. Urine microscopy showing red blood cell casts in a patient with active glomerulonephritis due to granulomatosis with polyangiitis (Wegener’s).

and/or accompanied by red blood cell casts (Figure 1). Abnormal urinalysisfindings,whenfollowedbypromptevaluationandinter-vention,provideanopportunitytominimizerenalinjuryanddam-agethatcanleadtopermanentlossofkidneyfunction.

Utility Continues Beyond Diagnosis

The urinalysis remains important even after a diagnosis of GPA orMPAhasbeenmade.Studieshaveshownthatalthoughglomerulonephritis is present in 20 percent of patients at diag-nosis,80percentwillgoontohaverenaldiseaseatsomepointduringtheirdiseasecourse(HoffmanGS,etal.Ann Intern Med. 1992;116(6):488-498). This means that ongoing vigilance for emergingglomerulonephritisiscritical.Suchvigilancecanbe ensured by including a uri-nalysis in the routine monitor-ing lab tests for patients with vasculitic diseases in which glomerulonephritis can occur. Another strategy we have used is to teach patients to performurinedipstickself-testing in between their rou-tine monitoring labs.

Oneconfoundingissueisthat after a patient has had glomerulonephritis,theurinewill not always clear com-pletely. It is not uncommon for proteinuria to persist as a result of damage that is not reflectiveofactivedisease.Hematuria and even red blood cell casts have also been found to persist in selected patients (MagreyMN,etal.Medicine. 2009;88(6):315-321). The interpretationofsuchfindingsmust factor in the creatinine measurement,thepresenceofotherdiseasefeaturesandwhetherthere has been a change from previous observations. If it remains unclearwhetherthefindingsareindicativeofactiveglomerulo-nephritis,arenalbiopsymayberequired.

Detecting Urothelial Toxicity from Cyclophosphamide

Urinalysis also plays a valuable role in monitoring for urothelial toxicityincyclophosphamide-treatedpatients.Duringtreatment,cyclophosphamide can cause bladder injury as a result of urothe-lial toxicity from the metabolite acrolein. Patients receiving daily cyclophosphamideshouldtakeitallatonceinthemorningandthendrinkalargeamountoffluidthroughoutthedaytominimizeurothelialexposuretotoxicmetabolites,andintermittentcyclo-phosphamide should be given with hydration and consideration for 2-mercaptoethanesulfonatesodium(MESNA).Newmicroscopichematuria in a patient receiving cyclophosphamide should raise suspicionforurothelialtoxicity.Bladderinjurycanmanifestsevere-lyashemorrhagiccystitisandalsorepresentsariskfactorforlater

development of transitional cell carcinoma. While limit-ing cyclophosphamide expo-sure to three to six months through use of staged regimens appears to have reducedtheriskofbladdercancer,theagentstillposespotential toxicities.

Urinalysis can detect those cyclophosphamide-treated patientswhoareatriskofbladdercancer,andthepresence of nonglomerular hematuria on urinalysis should prompt urological evaluation including cys-toscopy (Talar-Williams C,etal.Ann Intern Med. 1996;124(5):477-484).

The Urinalysis as a Biomarker

Inrheumatology,biomarkerdiscovery is an important

avenueofinvestigation,andourCenterforVasculitisCareandRe-searchisactivelyengagedinbiomarkerresearchhereandthroughthe Vasculitis Clinical Research Consortium. Although not new or fancy,theurinalysisexemplifiestheimpactasinglebiomarkercanhave in medicine. As we appropriately expand our range of bio-markers,wemustremembertheimportantrolethatthehumbleyetpowerful urinalysis has in the care of our patients.

Dr. Langford is Director of the Center for Vasculitis Care and Research as well as Vice Chair for Research, Department of Rheumatic and Immunologic Diseases. She can be reached at [email protected] or 216.445.6056.

Although not new or fancy, the urinalysis exemplifies the impact a single biomarker can have in medicine.


Osteoporosis Outcomes SnapshotsBy Chad Deal, MD

Topromotetransparencyandcontinuousimprovement,ClevelandClinichasbeenpublishingannualOutcomesbooksformorethanadozenofitsinstitutessince2007.The2012OutcomesbookfortheOrthopaedic&RheumatologicInstitutesharesdataondiverseclinicalmeasuresacrosstheDepartmentofRheumaticandImmunologicDiseases.Belowisasamplingofthebook’sdataforourCenterforOsteoporosisandMetabolicBoneDisease.

Formoreoutcomesfromourdepartment,visitclevelandclinic.org/outcomes.

Why it matters: Guidelines recommend pharmacotherapy for patients with low bone mass (T score < –2.5) at the hip or lumbar spine or with a 10-year absolute fracture risk (as calculated by FRAX) > 20 percent for major osteoporotic frac-ture or > 3 percent for hip fracture.

71%, 78%, 82% Percentage of patients with low bone massandhighfractureriskbyFRAX®

who were started on an osteoporosis medication within 90, 180 and 365 days, respectively, of their DXA bone scan*

*Among 816 patients during 2009-2012 not on treatment at the time of the DXA scan. Osteoporosis medications included bisphosphonates, denosumab, raloxifene and teriparatide.

74% Percentage of patients on glucocor-ticoidswith>20%10-yearriskformajor osteoporotic fracture (by FRAX) who were treated with an osteoporo-sis medication within one year of DXA*

*Fromdataamong1,476patientsreceivingglucocorticoidsformore than 90 days during 2010-2012 who were assessed by absolutefractureriskcategoriesformajorosteoporoticfracture.

Why it matters:NationalOsteoporosisFoundationguidelines for glucocorticoid-induced osteoporosis recommend therapy if a patient’s 10-year absolute riskformajorosteoporoticfractures(byFRAX)isgreater than 20 percent.

Related outcome: 72 percent of patients on gluco-corticoidswitha10-yearriskformajorosteoporoticfractures between 10 and 20 percent were treated withanosteoporosismedwithinoneyear,satisfyingthe stricter American College of Rheumatology guide-line recommendations.

Why it matters: Denosumab is indicated for patients with low bone mass at high risk for fracture. Once therapy is started, guidelines recommend treatment at six-month intervals; delays in treatment result in loss of effect.

Related outcome: A third dose of deno-sumab was given to 92 percent of patients within 180 ± 60 days of the second dose.

Percentage of denosumab recipients who received a second dose of the medication at 180 ± 60 days after thefirstdose*

*Among 59 patients during 2010-2012.

Dr. Deal is Director of the Center for Osteoporosis and Metabolic Bone Disease as well as Vice Chair for Quality and Outcomes in the Department of Rheumatic and Immunologic Diseases. He can be reached at [email protected] or 216.444.6575.

>99% Percentage of patients treated with

zoledronic acid who had vitamin D

testing within 90 days before infusion**Among1,411patientsduring2010-2012.

Why it matters: Zoledronic acid (Reclast®) infusion for osteoporosis may be associated with hypocalcemia after infusion. Patients withhypovitaminosisDareathighriskfor hypocalcemia. A vitamin D level is deemed standard of care in patients prior to infusion.

80%


Making a Difference for Patients with a Multidisciplinary Lupus Clinic By Howard R. Smith, MD, and Mehrnaz Hojjati, MD

Case Presentation

A 48-year-old man presented to his primary care physi-cian reporting the following symptoms over the prior month: fatigue,low-gradefevers,15-pound

weightloss,new-onsetshortnessofbreath,numbness/tinglingovertheleftfoot,andpolyarthralgiainvolvingthemetacarpophalangealandproximalinterphalangealjoints,wrists,shouldersandknees.His history was notable for hypertension and tobacco chewing for 20years,andhisfamilyhistorywasnotableforlupus(systemiclupuserythematosus;SLE)inanaunt.PreliminarylabevaluationbyhisprimarycarephysicianshowedanelevatedESR(87mm/hr)andpositiveanti-nuclearantibody(ANA)findings(1:640titer)(Figure 1).

He was referred to Cleveland Clinic’s Center for Vasculitis Care andResearch,wherefurthertestingrevealedelevatedanti-dsDNAantibodies,leukopeniaandthrombocytopenia,alowC3level,proteinuria,andanti-cardiolipinIgMantibodies.Serologyforanti-neutrophilcytoplasmicantibodies,cryoglobulins,hepatitisandHIVwasnegative,aswasserumproteinelectrophoresis.ChestCTrevealedpulmonaryemboli(Figure2),andEMGshowedmoderatesensory axonal neuropathy with a mononeuritis multiplex pattern.

Anticoagulationwasinitiated,alongwithmethylprednisolone,andthe patient had same-day appointments at Cleveland Clinic to seearheumatologistwithlupusexpertiseattheLupusClinic,anephrologistforarenalbiopsy,andaneurologistandaninfectiousdisease specialist to rule out lupus mimics. Lupus nephritis and lupusvasculitiswereconfirmedonfurtherevaluationandrenalbiopsy. A coordinated course of therapy was initiated that included pulse corticosteroids and additional immunosuppressive therapy with monthly IV cyclophosphamide.

The Case for a Streamlined Multidisciplinary Approach

The above vignette represents the complexity of symptoms with whichsomeSLEpatientspresent,underscoringtheimportanceof a multidisciplinary approach to address all medical aspects of these patients’ cases and fully optimize their care. This case ex-emplifiesthetypeofpatientevaluatedandmanagedatClevelandClinic’snewmultidisciplinaryLupusClinic,whichwasestablishedby the Department of Rheumatic and Immunologic Diseases to integratethemanagementofpatientswithSLEandprovidecom-prehensive,leading-edgecare.

ForpatientswithcomplexSLEcases,theLupusClinicprovidesaccess to the department’s team of rheumatologists specializing in SLEalongwithstreamlinedaccesstosubspecialistsinotherdis-ciplines,includingnephrologists,dermatologists,neurologistsandpreventive cardiologists (see sidebar for additional case example). The clinic offers both consultative services and long-term manage-ment,includingtreatmentsdirectedatallofSLE’sdiversefacets,suchasarthritis,dermatitis,nephritisandcerebritis.

Same-dayaccesstootherspecialistproviderswithexpertiseinSLEinvolvingotherorgans,suchasthekidneysandtheskin,isacornerstone of the Lupus Clinic. It serves to ensure both maximum convenience for patients and care that addresses all aspects of theircondition,whetheritbeSLEorrelatedconnectivetissuedis-eases such as overlap syndromes.

Going Beyond the Diagnosis

TheLupusClinicprovidescarethatgoesbeyondthediagnosis,focusing on routine follow-up appointments that are tailored to patients’needsanddiseasecomplexity.Forinstance,patientswhoareathigherriskforfrequentdiseaseflaresorend-organinvolvement

Same-day access to other specialists with expertise in SLE involving other organs is a cornerstone of the Lupus Clinic.

Figure 1.Anti-nuclearantibodyindirectimmunofluorescencestaining showing a nucleolar pattern.


(e.g.,renalcomplications,whichareoftenclinicallyasymptom-atic) are monitored via simple urine and blood tests at routine follow-up visits. Lupus patients evaluated in the clinic are also offeredscreeningformodifiablecardiovascularriskfactors,through Cleveland Clinic’s state-of-the-art Preventive Cardiol-ogyProgram,aswellaslifestylemodificationcounselingandtherapeuticguidancebasedontheirriskstratification.

Additionally,theLupusClinicoffersinterestedpatientsthe opportunitytoenrollinClevelandClinic’slupusregistry,whichisdirectedbyMehrnazHojjati,MD,intheDepartmentofRheumaticandImmunologicDiseases(seedetailsinbiobank-ingarticleonpages3-4).ThecliniclikewisegivespatientseasyaccesstoinvestigationalclinicaltrialsinSLEandotherchallengingautoimmunediseases,facilitatedbyon-siteclinicalresearch coordinators. As the Lupus Clinic’s cumulative patient basegrows,welookforwardtosharingresearchinsightsthatemerge from these trials. Figure 2. Chest CT showing saddle pulmonary emboli.

Drs. Smith and Hojjati are staff physicians in the Department of Rheumatic and Immunologic Diseases whose specialty interests include lupus. Dr. Smith can be reached at [email protected] or 216.444.4555. Dr. Hojjati can be reached at [email protected] or 216.444.5624.

A Case Study in CollaborationA 29-year-old woman presented to her primary care physician reportingsixweeksofswellingofthefingersandknees,facialrash,andstabbingpaininthechestwithbreathing.Examina-tionconfirmedpleurisyandedema(Figure3),andlabresultsrevealedanemia,leukopeniaandpositiveANAfindings.

ShewasreferredtoClevelandClinic’sLupusClinicforfurtherevaluationandtreatment.AttheLupusClinic,shewasdi-agnosedwithSLEandfoundtoalsohavepericarditisandproteinuria.Shewasstartedonoralsteroidtherapyandfur-therevaluatedbysubspecialistsincardiology,nephrologyanddermatology.Additionaltestingwasconducted,includingakidneybiopsy.

Herphysiciansconferredwiththereferringphysician,anda coordinated course of therapy was proposed. It was de-cided to initiate treatment with the IV immunosuppressants cyclophosphamide and methylprednisolone followed by oral hydroxychloroquine,prednisoneandmycophenolatemofetil.The patient received detailed education about her disease and the proposed treatment. After her questions and concerns wereaddressed,treatmentstarted.Shefaredwell,withrapid

resolutionofthearthritis,rashandpericarditis.Herkidneyfunctionimproved,andsixmonthslatershehadonlymildproteinuriaandmildrenalinsufficiency.

Figure 3. Radiograph showing pleural and pericardial effusion in the case patient.


The Fibromyalgia Clinic:Why a Specialized Multidisciplinary Approach Makes Sense for Fibromyalgia and Chronic Fatigue SyndromeBy Carmen Gota, MD, and Sara Davin, PsyD

About 4 percent of the general population is estimated to suffer fromfibromyalgia,which is probably an underestimate of the condition’s actual prevalence.

Intertiaryrheumatologypractices,approximately20to30percent ofpatientsseenarediagnosedwithfibromyalgia.

A Quintessentially Clinical Diagnosis

Thediagnosisoffibromyalgiaisclinical.Itisbasedonthecombi-nationofchronicwidespreadpain,fatigueandnonrestorativesleepaswellasmanyothersomaticcomplaints,suchasheadaches,memoryandconcentrationimpairment,irritablebowelsymptoms,urinaryfrequencyanddizziness.Individualswithfibromyalgiatypi-callyreportpainthatisworsenedatnight,withsittingandafterexercise.Mostpatientsalsoreportsymptomsofdepression,anxi-ety and other mood problems. To illustrate just how widespread theaforementionedsymptomsareinthispopulation,Table1liststheirprevalenceamongthefirst305patientsinClevelandClinic’sFibromyalgia Clinic cohort.

Themaladaptivechronicstressresponsethatleadstofibromyalgiaresultsfromacombinationoffactors,includinggeneticpredisposi-tion,personalitytraits,environment,traumaticeventsandemotionalproblems. These factors trigger and contribute to the persistence ofstressandthusoffibromyalgiasymptoms.Althoughtheclinicalpresentationisthesame,thespecificcausalpathwaysoffibromy-algiadifferamongindividualpatients.Thus,eachpatientmaybeconceptualizedashavingauniquefibromyalgia“fingerprint.”

Pharmacotherapy: Important but Not Adequate

Threedrugshavebeenapprovedforthemanagementoffibro-myalgia:pregabalinandtheserotonin-norepinephrinereuptakeinhibitors milnacipran and duloxetine. In randomized controlled studies,halfthepatientstreatedreportanimprovementinpainofapproximately 30 percent. Responders report an average 2-point decreaseinpainonan11-pointvisualanalogscale.However,re-searchshowsthatforpatientswithfibromyalgiatofeelsignificantlyimproved,atleasta50percentimprovementinpainisneeded.Notably,othersymptomsbesidespain,suchasfatigue,sleepandmood,needtobeaddressedandimproveaswell.

Pharmacotherapyremainsanimportantcomponentoffibromyalgiatreatment,butitisinsufficientasanisolatedintervention,inviewofthecondition’smultifactorialanduniqueetiology,asoutlinedabove. A multidisciplinary approach is necessary.

Interdisciplinary Offerings to Address Broad Patient Needs

Becauseofthesechallenges,ClevelandClinic’sOrthopaedic&Rheumatologic Institute and its Neurological Center for Pain col-laboratedtodevelopaspecializedfibromyalgiaclinicinearly2012.The goal of the Fibromyalgia Clinic is to offer multidisciplinary care topatientswithfibromyalgiaandchronicfatiguesyndrome,aswellastohelpadvanceknowledgeaboutthesedifficultconditionsthrough research and education.

Eachpatientisevaluatedbyspecialistsinrheumatology,psychologyand physical therapy to obtain a comprehensive evaluation regard-ingsymptoms,deconditioning,stressors,depression,mood,sleepdisorders and maladaptive behaviors in response to pain and fatigue. Afterthisinitialevaluation,patientsareinvitedtoparticipateinourtwo distinctive treatment offerings:

•One-Day Intensive Fibromyalgia Program. In the summer of 2013,theFibromyalgiaCliniclaunchedtheOne-DayIntensiveFibromyalgiaProgram,designedforallpatientswithfibromyal-gia. The program immerses participants in a day of education relatedtofibromyalgia,addressingthemaladaptivestressre-sponsesthatleadtofibromyalgiaandreviewingtheeffectivenessof available interventions. Patients are provided with essential tools,approachesandcopingskillsforself-managementoffibro-myalgia. Interactive sessions are led by staff from our program’s threedisciplines—rheumatology,physicaltherapyandpsychol-ogy—andparticipantsaregiveneducationalmaterialsandresources to use at home.

• Fibromyalgia Management Program. TheFibromyalgiaMan-agementProgramisacoordinated,multidisciplinarytreatmentplan that includes participation in a cognitive-behavioral therapy group.Targetsformodificationaremaladaptivethoughts,be-liefsandattitudestowardpain,andskills-buildinginhealthybehaviorsisemphasized.Physicaltherapistsworkwithpatients

Each fibromyalgia patient may be conceptualized as having a unique fibromyalgia “fingerprint.”


TheFibromyalgiaClinicteam:CaraSiebert,PT;SaraDavin,PsyD,AssociateDirector;TiffanyClark,MSN,NP-C;CarmenGota,MD,Director;andMaribethGibbon,PT.

to develop a home exercise program tailored to each patient’s baselineabilities,andtheyrecommendoutpatientphysicaltherapy and follow-up visits to monitor progress. Patients return regularly (approximately every three months) for medication and medicalmanagementintheclinic,whentreatmentprogressisfurther assessed.

New and Evolving Initiatives

The Fibromyalgia Clinic staff believes strongly in the value of edu-cationandadvocacyforthefibromyalgiapopulation.Ourteamis developing a newsletter for patients to provide education and updatesonscientificresearchandnewdevelopmentsrelatedtofibromyalgia.Wearealsodevelopingportable,electronicmethodsof education and intervention for patients established in the Fibro-myalgiaClinic.Finally,weareconductingextensivedatacollectionthroughourfibromyalgiaregistry,whichsofarhasenlistedmorethan700patients.Ourmajorinterestsforresearchusingthesedata include identifying patient subsets and creating pathways to reduce the cost of care and improve outcomes.

Dr. Gota is Director of the Fibromyalgia Clinic and a staff physician in the Department of Rheumatic and Immunologic Diseases. She can be reached at [email protected] or 216.444.0564.

Dr. Davin is Associate Director of the Fibromyalgia Clinic and a psychologist in the Neurological Center for Pain in Cleveland Clinic’s Neurological Institute. She can be reached at [email protected] or 216.445.3977.

Table 1. Prevalence of Common Fibromyalgia Symptoms in the First 305 Patients in the Fibromyalgia Clinic Cohort

Fatigue 98.7%

Widespread pain for three months or more 97.1%

Current depression (PHQ-9 score > 10) 88.6%

Unrefreshing sleep 85.8%

Headaches 82.5%

Difficultyconcentrating 79.5%

Memorydifficulty 75.5%

Urinary frequency 67.5%

Constipation alternating with diarrhea 61.8%

Current severe or moderate-to-severe depression(PHQ-9score≥15)

45.8%

Anxiety 41.8%

PHQ-9 = Patient Health Questionnaire-9

Our fibromyalgia registry has so far enlisted more than 700 patients. We plan to use the registry’s extensive data to identify patient subsets and create pathways to reduce the cost of care and improve outcomes.


Biologic Therapies Summit and Vasculitis Symposium Build Audience and Expertise for 2015 and Beyond

What’sbothdomesticandinternational,liveandonline,andfivetimes a bigger draw than when it started a decade ago?

IfyouguessedtheBiologicTherapiesSummitfromClevelandClinic’sR.J.FasenmyerCenterforClinicalImmunology,youguessedright.InMay,thecenterofferedthebiennialsummitforthefifthtime,inconjunction with the 22nd Annual Cleveland Review of Rheumatic Diseases.Thethemeofthisyear’sthree-dayCME-certifiedcoursewas“LessonsLearnedfromtheFirstDecade,FocusingonNewTargets and Agents.”

“The summit has grown from a small meeting of about 100 people todrawingmorethan500overtheyears,withattendeesthisyearfrommorethan30statesandninecountries,”saysthesummit’sprogramdirector,LeonardCalabrese,DO,DirectoroftheR.J.Fasenmyer Center for Clinical Immunology in the Department of RheumaticandImmunologicDiseases.Manyattendeeshavebeentoallfivesummits,headds.

“We offer three days of intense teaching in what many say is the finestclinicalmeetinginrheumatologytheyhaveeverattended,”saysDr.Calabrese.“Someoftheworld’sleadingauthoritiesinbio-logicsparticipate,includingrheumatologists,gastroenterologists,dermatologists and neurologists. Everyone shares information on theuseofbiologicsintheirrespectivefields.”

This year’s faculty was evenly split between Cleveland Clinic ex-pertsandtheircolleaguesfromaroundthenationandtheworld,includingspeakersfromGreeceandIreland.Afterkickingoffthesummitwithareviewofrecentbasicsciencebreakthroughsinbiologicsandthepotentialclinicalimplications,theyshiftedto

in-depthsessionsonapprovedagents,newagents,predictingtox-icity,clinicalcontroversiesandnewindications.

Reaching Beyond Ohio — and Beyond Real Time

ThoughthesummitisheldinCleveland,itsreachextendsfarbe-yond,astensofthousandsofmedicalprofessionalsworldwidehaveviewedsomeorallofitonline(seebox),whereit’savailableondemandasaseriesofCME-certifiedwebcastsrangingfrom15to60minutesinlength.ThewebcastswillremainpostedforfreeCMEcredituntiltheBiologicTherapiesVISummit,plannedfor2015.

Thisyear’sBiologicTherapiesVSummitalsowasavailableforreal-timeviewing,andDr.Calabresehopestooffermore-targetedworldwide simulcasts in 2015 and beyond. Possible examples includesimulcastsfocusingonthereactivationofhepatitisBinChinaorthereactivationoftuberculosisintheMiddleEast.

Vasculitis Merits a Dedicated Precourse Symposium

OnesignofthesuccessoftheBiologicTherapiesSummitisthe interest in the daylong symposium on vasculitis that has immedi-atelyprecededthepasttwosummits,in2011and2013.Nearly300 attendees from diverse medical and surgical specialties partici-patedinthisyear’ssymposium,entitled“LargeVesselVasculitis,EosinophilicGranulomatosiswithPolyangiitis(Churg-StraussSyn-drome),andOtherUniqueVasculitides.”Thisfocuscomplementedtheemphasisonsmallvesselvasculitisofthe2011symposium,entitled“NewDirectionsinSmallVesselVasculitis:ANCA,TargetOrgans,Treatment,andBeyond.”

Leonard Calabrese, DO


Missed the Courses?

No problem. Free CME-certified webcasts of Biologic

Therapies V Summit sessions are available now in

convenient segments (some as short as 15 minutes) at

ccfcme.org/RheumCME. And free CME-certified online

monographs based on the summit and the precourse

symposium on large vessel vasculitis are coming soon

to the same website.

These activities have been approved for AMA PRA Category 1 credit™.

“Wesoughttohighlightthediversityofvasculiticdiseases,”explainsCarolLangford,MD,MHS,whoservedasthesymposium’sactivityco-directorwithDr.CalabreseandGaryHoffman,MD,MS.“Thefamilyofvasculiticdiseasesisquitebroad,sotherearealotofexciting things to discuss.”

“Thiscourseisauniqueandimportantofferinginwhichweseektoprovide multidisciplinary education about vasculitis from experts at ClevelandClinicandthroughouttheworld,”saysDr.Langford,Di-rector of Cleveland Clinic’s Center for Vasculitis Care and Research. ShenotesthatthishassofarincludedguestfacultyfromEngland,Ireland,GermanyandCanada.

Manyregistrantsattendedboththesummitandthevasculitispre-course,andDr.Langfordanticipatesthatthetwowillcontinuetobeheldinconjunction,includingin2015.“It’sagreateducationalopportunitytocomeforboth,”shesays.

“Education in vasculitis is one of our foremost missions in the Cen-terforVasculitisCareandResearch,”saysDr.Langford.“Thesesymposiaallowustoreachouttoaverylargeaudience,includingattendeesoftheBiologicTherapiesSummit.Althoughmanyvas-culiticdiseasesareuncommon,itisanimportantdiseaseareaforrheumatologists,onewhereknowledgeandawarenessmakea tremendous difference to patients and their outcomes.”

“The Biologic Therapies Summit offers three days of intense teaching in what many say is the finest clinical meeting in rheumatology they have ever attended.”

— Program Director Leonard Calabrese, DO

Carol Langford, MD, MHS


Cleveland Clinic Plays Exclusive Role in Updating Musculoskeletal Volume of The Netter Collection

“Every medical student and resident across many decades remembers the Netter publications and how valuable they have been as an aid to understanding anatomy and basic science.”

— Chad Deal, MD, section editor for the rheumatic and metabolic

diseases portions of The Netter Collection’s revised Musculo-

skeletal System volume

ClevelandClinic’sOrtho-paedic&RheumatologicInstitute partnered with the publisher of The Netter Collection of Medical Illus-trations to comprehensively update the series’ recently published three-part Musculoskeletal System volume. The collaboration representsthefirsttimeamedical center has provid-ed exclusive clinical content

guidance for a volume of this iconic collection of anatomic illustra-tions that has educated generations of medical students.

The effort helps complete the second edition of the nine-volume collection,markingthefirstrevisionsinceitsmid-20th-centuryintroductionbyreveredphysicianandmedicalillustratorFrankH.Netter,MD.

Co-editors of the second edition’s Musculoskeletal System volume areJosephP.Iannotti,MD,PhD,ChairofClevelandClinic’sOrtho-paedic&RheumatologicInstitute,andRichardD.Parker,MD,ChairoftheDepartmentofOrthopaedicSurgery.Theyenlistedtheassistanceof50ClevelandClinicstaff,mostlyfromtheOrthopaedic&RheumatologicInstitute.

“Ourpublishingpartner,Elsevier,wantedtoensurethattheupdatedvolume retained the appeal The Netter Collectionhasalwayshad,”saysDr.Parker.“Sowesharedamutualcommitmenttothesameprecision,clarityandproficiencyinpresentingcomplexconceptssimply.”

SpecificRoleforRheumatology

AmongtheexpertsenlistedwasChadDeal,MD,ViceChairforQualityandOutcomesintheDepartmentofRheumaticandImmu-nologic Diseases. Dr. Deal served as section editor for the compre-hensive sections on rheumatic diseases and metabolic diseases in Part III of the volume (Biology and Systemic Diseases),drawingonthe expertise of more than a dozen Department of Rheumatic and ImmunologicDiseasescolleaguesandofRonaldMidura,PhD,oftheDepartmentofBiomedicalEngineering.

Theirchargewastoupdateandrefreshthevolume’stext,addmodernimagingwhereappropriate,organizethecontentinkeep- ingwithmodernpracticeandmedicalinstruction,andguide illustration updates where needed. The latter were carried out by ateamofmedicalillustratorsworkingintheNetterstyle(Dr.Netterdied in 1991).

The Pleasures of Revisiting an Old Friend

“Every medical student and resident across many decades now remembers the Netter publications and how valuable they have beenasanaidtounderstandinganatomyandbasicscience,”notesDr.Deal.“ItwasapleasuretoworkwiththeNetterteamtoupdateand expand the rheumatology content for this publication.”

“The medical illustrations in The Netter Collection are second to none,”addsfellowcontributorAbbyAbelson,MD,ChairoftheDepartment of Rheumatic and Immunologic Diseases. “We were honoredtopartneronthisvaluedresource,makingitapartoftheeducationallegacyoftheOrthopaedic&RheumatologicInstituteand Cleveland Clinic.”

The Netter Collection’s second edition is available in electronic and printformatswiththehallmarkcoversthatledthecollectiontobeaffectionatelyknownasthe“GreenBooks.”TheMusculoskeletal Systemvolume(volume6)consistsofthreeparts—Upper Limb (PartI),Spine and Lower Limb (Part II) and Biology and Systemic Diseases(PartIII)—releasedbetweenlate2012andearly2013.


Study Title Site Principal Investigator

ACR/EULAR Study to Develop Classification and Diagnostic Criteria for Primary Systemic Vasculitis Leonard Calabrese, DO

Phase 1, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Tolerability of MEDI-551 in Scleroderma

Soumya Chatterjee, MD

Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of Tocilizumab vs. Placebo in Patients with Systemic Sclerosis


Prospective, Randomized, Placebo-Controlled, Double-Blind Study of Macitentan in Patients with Ischemic Digital Ulcers Associated with Systemic Sclerosis


International Costs and Utilities Related to Osteoporotic Fractures Study (ICUROS) Chad Deal, MD

Osteoporosis Treatment Initiation in Treatment-Naive Patients with a T-Score < –2.5 Chad Deal, MD

Lymphoproliferative Disorders in Patients with Primary Immunodeficiency James Fernandez, MD, PhD

Study of Fibromyalgia Outcomes Carmen Gota, MD

WAVE3 Expression in Patients with Fibromyalgia and Chronic Fatigue Syndrome Carmen Gota, MD

Defining Mechanisms of Atherosclerosis in Autoimmune Diseases Rula Hajj-Ali, MD

Long-Term Outcomes of Patients with Reversible Cerebral Vasoconstriction Syndrome (RCVS) Rula Hajj-Ali, MD

The INTERnational Study of Primary Angiitis of the CEntral Nervous System (INTERSPACE) Rula Hajj-Ali, MD

Development of a Web-Based Data Management System for the Study of Primary Angiitis of the Central Nervous System

Rula Hajj-Ali, MD

Unique Vulnerabilities of the Thoracic Aorta: Autoimmune Large Vessel Vasculitis Gary Hoffman, MD

Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Efficacy and Safety of PF-04236921 in Systemic Lupus Erythematosus

Mehrnaz Hojjati, MD

Systemic Lupus Erythematosus Biobank Study Mehrnaz Hojjati, MD

Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen or Naproxen (PRECISION) Elaine Husni, MD

COMPASS Study: Cardiometabolic Outcome Measures in Psoriatic Arthritis Study Elaine Husni, MD

Ethnographic Research Study: Osteoarthritis and Obesity Pilot Project Elaine Husni, MD

Investigating the Efficacy of Synvisc-One as Adjunctive Therapy for Patients with Knee Osteoarthritis Requiring Physical Therapy

Elaine Husni, MD

Serial Assessment of the Immunologic Profile in Patients with Granulomatosis with Polyangiitis (Wegener’s) Atul Khasnis, MD

Serial Assessment of the Immunologic Profile in Patients with Hepatitis C Infection and Cryoglobulinemic Vasculitis

Atul Khasnis, MD

Vasculitis Clinical Research Consortium (VCRC): Longitudinal Protocols and Genetic Repository One-Time DNA for Takayasu’s Arteritis, Giant Cell Arteritis, Eosinophilic Granulomatosis with Polyangiitis (Churg-Strauss), Polyarteritis Nodosa, Granulomatosis with Polyangiitis (Wegener’s) and Microscopic Polyangiitis

Carol Langford, MD

Concurrent Pilot Studies in Giant Cell Arteritis and Takayasu’s Arteritis to Examine Abatacept in Large Vessel Vasculitis (AGATA)

Carol Langford, MD

Plasma Exchange and Glucocorticoid Dosing in the Treatment of ANCA-Associated Vasculitis (PEXIVAS) Carol Langford, MD

International, Open-Label, Randomized Controlled Trial Comparing Rituximab with Azathioprine as Maintenance Therapy in Relapsing ANCA-Associated Vasculitis (RITAZAREM)

Carol Langford, MD

International Collaborative Study of Susac Syndrome Robert Rennebohm, MD

Relapse Rate with Long-Term Maintenance Therapy for Granulomatosis with Polyangiitis (Wegener’s) Alexandra Villa-Forte, MD

Adult-Onset Periodic Disease Associated with NOD2/CARD15 Gene Mutation Qingping Yao, MD, PhD

Abatacept for Patients with Inflammatory Arthritis Associated with Sjögren’s Syndrome Qingping Yao, MD, PhD

Featured Clinical ResearchBelowarehighlightsamongthedozensofclinicalresearchstudieswithin the Department of Rheumatic and Immunologic Diseases.

Fordetailsonagivenstudy,contacttheprincipalinvestigator (see clevelandclinic.org for a directory with contact information).


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Rheumatology ConnectionsAn Update for Physicians | Fall 2013

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Rheumatology Connections - Cleveland Clinic · 2013. 12. 20. · collaboration makes me feel honored to work with my 32 rheumatology colleagues at Cleveland Clinic. I hope you enjoy